Respiratory syncytial virus (RSV) infection is the primary cause of respiratory infection in young children, causing >120,000 hospitalizations in the US annually. RSV vaccine development has been hampered by the history of a failed vaccine trial in the early 1960s in which vaccinated children were not protected against subsequent natural infection but rather experienced more severe disease. Subsequent experiments in animal models and human subjects suggest the occurrence of severe RSV disease correlates with the induction of virus-specific Th2 CD4 T cells and eosinophil recruitment and degranulation. The G glycoprotein of RSV and killed virus vaccines containing adjuvants such as alum induce these types of immune responses associated with the vaccine-enhanced disease syndrome. In these studies, we have examined the role of the both the antigen, FI-RSV, and immune response to this antigen as well RSV itself to gain insight into immunopathology and enhanced-disease. With our recent stablization of the RSV F protein in the prefusion confirmation, we have identified epitopes that are expressed only on the prefusion form of the F protein. We have applied these findings to better understanding the conformation of the F protein in the FI-RSV vaccine and the specificity of the immune response generated towards the vaccine. Additionally, we have examined the contribution of CD4 T cells and CD8 T cells to immunopathology and viral clearance. CD4 T cells can influence and regulate the function of other immune effectors including CD8 T cells. In addition to the potential role of Th2 CD4 T cells in RSV pathogenesis as mentioned above, T regulatory cells have properties that suggest they may be important in RSV immunity and pathogenesis. We are currently evaluating the recruitment of regulatory T cells during primary and secondary infections.